Placebo-controlled Randomized Clinical Trial Research Articles

Oral Minoxidil vs Topical Minoxidil for Male Androgenetic Alopecia

There has been increased interest in low-dose oral minoxidil for androgenetic alopecia (AGA) treatment. However, the efficacy of oral minoxidil for male AGA is yet to be evaluated in comparative therapeutic trials. To compare the efficacy, safety, and tolerability of daily oral minoxidil, 5 mg, vs twice-daily topical minoxidil, 5%, for 24 weeks in the treatment of male AGA. This double-blind, placebo-controlled randomized clinical trial was conducted at a single specialized clinic in Brazil. Eligible men with AGA aged 18 to 55 years classified using the Norwood-Hamilton scale as 3V, 4V, or 5V were included and randomized. Data were collected from January to December 2021, and data were analyzed from September 2022 to February 2023. Participants were randomized 1:1 into 2 groups: oral minoxidil, 5 mg, daily and topical placebo solution; or 1 mL of topical minoxidil, 5%, twice daily and oral placebo for 24 weeks. The primary outcome was change in terminal hair density on the frontal and vertex regions of the scalp. The secondary outcomes were change in total hair density and photographic evaluation. Among 90 enrolled participants, 68 completed the study; of these, the mean (SD) age was 36.6 (7.8) years. A total of 33 participants were enrolled in the oral minoxidil group and 35 in the topical treatment group. Both groups were homogenous in terms of demographic data and AGA severity. For the frontal area, the mean change from baseline to week 24 between groups was 3.1 hairs per cm2 (95% CI, -18.2 to 21.5; P = .27) for terminal hair density and 2.6 hairs per cm2 (95% CI, -10.3 to 15.8; P = .32) for total hair density. For the vertex area, the mean change from baseline to week 24 was 23.4 hairs per cm2 (95% CI, -0.3 to 43.0; P = .09) for terminal density and 5.5 hairs per cm2 (95% CI, -12.5 to 23.5; P = .32) for total hair density. According to the photographic analysis, oral minoxidil was superior to topical minoxidil on the vertex (24%; 95% CI, 0 to 48; P = .04) but not on the frontal scalp (12%; 95% CI, -12 to 36; P = .24). The most common adverse effects in the oral minoxidil group were hypertrichosis (22 of 45 [49%]) and headache (6 of 45 [14%]). In this study, oral minoxidil, 5 mg, once per day for 24 weeks did not demonstrate superiority over topical minoxidil, 5%, twice per day in men with AGA. Brazilian Registry of Clinical Trials Identifier: RBR-252w9r.

Extracorporeal Shockwave for Intermittent Claudication and Quality of Life

Intermittent lower limb claudication limits function and quality of life. Supervised exercise programs are not readily available, and a noninvasive alternative is needed. To assess extracorporeal corporeal shockwave therapy in improving quality of life in patients with claudication. In this double-blind, placebo-controlled randomized clinical trial, patients in the outpatient setting at a single tertiary center for vascular surgery were randomized in a 1:1 ratio to extracorporeal shockwave therapy or placebo therapy with no shockwaves delivered. Recruitment was between June 2015 and January 2020, with 12-week follow-up ending in March 2020. A convenience sample of patients with claudication and conservative treatment requirements who refused or were unable to participate in supervised exercise were eligible. Patients receiving anticoagulation therapy or with an active cancer were excluded. Of 522 patients screened, 389 were eligible, 138 were enrolled, and 110 completed follow-up and were included in the primary analysis. Statistical analysis was completed by May 2021. In the intervention group, patients received 100 impulses of 0.1mJ/mm/cm2 in an area of the gastrocnemius muscle 3 times weekly for 3 weeks. The steps for treatment were replicated for the control group without delivering the treatment. The primary outcome was the Physical Functioning domain of the 36-item Short-Form Quality of Life Questionnaire at 12-week follow-up. Secondary outcomes included walking distances, ankle brachial pressure index, and other quality-of-life measures. Of 138 patients recruited and randomized, 92 (67%) were male, and the mean (SD) age of the study population was 67 (9.6) years. The intervention group had a significantly higher physical function score at 12 weeks (estimated median difference 3.8; 95% CI, 0.0-7.7; P = .03). However, this significance did not remain when adjusting for covariates. At 12 weeks, the intervention group had significantly longer pain-free and maximum walking distances (pain-free estimated median difference, 34.1, 95% CI, 11.4-56.8; P = .004; maximum estimated median difference, 51.4; 95% CI, 10.7-86.5; P = .01). To our knowledge, this is the first double-blind, placebo-controlled, randomized clinical trial to consider extracorporeal shockwave therapy for the management of intermittent claudication. It demonstrated efficacy for walking distances, may have a positive effect on quality of life, and may provide a safe, noninvasive alternative therapy for patients with intermittent claudication. ClinicalTrials.gov Identifier: NCT02652078.

Editorial Expression of Concern: The effect of alpha lipoic acid on uterine wound healing after primary cesarean section: a triple-blind placebo-controlled parallel-group randomized clinical trial.

Editorial Expression of Concern: The effect of alpha lipoic acid on uterine wound healing after primary cesarean section: a triple-blind placebo-controlled parallel-group randomized clinical trial.

Morbidity After Mechanical Bowel Preparation and Oral Antibiotics Prior to Rectal Resection

Surgical site infections (SSIs)-especially anastomotic dehiscence-are major contributors to morbidity and mortality after rectal resection. The role of mechanical and oral antibiotics bowel preparation (MOABP) in preventing complications of rectal resection is currently disputed. To assess whether MOABP reduces overall complications and SSIs after elective rectal resection compared with mechanical bowel preparation (MBP) plus placebo. This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 3 university hospitals in Finland between March 18, 2020, and October 10, 2022. Patients aged 18 years and older undergoing elective resection with primary anastomosis of a rectal tumor 15 cm or less from the anal verge on magnetic resonance imaging were eligible for inclusion. Outcomes were analyzed using a modified intention-to-treat principle, which included all patients who were randomly allocated to and underwent elective rectal resection with an anastomosis. Patients were stratified according to tumor distance from the anal verge and neoadjuvant treatment given and randomized in a 1:1 ratio to receive MOABP with an oral regimen of neomycin and metronidazole (n = 277) or MBP plus matching placebo tablets (n = 288). All study medications were taken the day before surgery, and all patients received intravenous antibiotics approximately 30 minutes before surgery. The primary outcome was overall cumulative postoperative complications measured using the Comprehensive Complication Index. Key secondary outcomes were SSI and anastomotic dehiscence within 30 days after surgery. In all, 565 patients were included in the analysis, with 288 in the MBP plus placebo group (median [IQR] age, 69 [62-74] years; 190 males [66.0%]) and 277 in the MOABP group (median [IQR] age, 70 [62-75] years; 158 males [57.0%]). Patients in the MOABP group experienced fewer overall postoperative complications (median [IQR] Comprehensive Complication Index, 0 [0-8.66] vs 8.66 [0-20.92]; Wilcoxon effect size, 0.146; P < .001), fewer SSIs (23 patients [8.3%] vs 48 patients [16.7%]; odds ratio, 0.45 [95% CI, 0.27-0.77]), and fewer anastomotic dehiscences (16 patients [5.8%] vs 39 patients [13.5%]; odds ratio, 0.39 [95% CI, 0.21-0.72]) compared with patients in the MBP plus placebo group. Findings of this randomized clinical trial indicate that MOABP reduced overall postoperative complications as well as rates of SSIs and anastomotic dehiscences in patients undergoing elective rectal resection compared with MBP plus placebo. Based on these findings, MOABP should be considered as standard treatment in patients undergoing elective rectal resection. ClinicalTrials.gov Identifier: NCT04281667.

The Effect of Oral Adenosine Triphosphate (ATP) Supplementation on Anaerobic Exercise in Healthy Resistance-Trained Individuals: A Systematic Review and Meta-Analysis.

Adenosine triphosphate (ATP) is an energy and signaling molecule. It is synthesized endogenously and can be taken as an oral supplement. This review aimed to identify the effects of oral ATP supplementation on anaerobic exercise in healthy resistance-trained adults. A systematic review and meta-analysis were performed based on the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) criteria. The inclusion criteria were articles published from 2000 to 2022, with anaerobic variables (maximal strength, maximum repetitions, and maximum anaerobic power) measurable in healthy adults with experience in resistance training, only randomized placebo-controlled clinical trials (RCTs), and with the acute (a single dose 30 min to 24 h before the tests) and/or chronic (>1 day) oral supplementation of ATP. A total of five RCTs with 121 adult men were included. The oral ATP supplementation achieved significantly greater gains in maximal strength compared with the placebo (PL) (MD = 8.13 kg, 95%CI [3.36-12.90], p < 0.001). Still, no differences were observed in the maximum number of repetitions or the maximum anaerobic power. Furthermore, 400 mg of ATP showed improvement in anaerobic exercise regardless of the duration of the supplementation protocol. In conclusion, supplementation with 400 mg of ATP doses can improve maximal muscle strength in resistance-trained men.

The Effects of Probiotic Supplementation on Functional Constipation Following Colonoscopy: A Double-blinded Randomized Controlled Trial

Background:: Functional constipation (FC) is characterized by infrequent and hard bowel movements, often accompanied by difficulty and pain during the passage. It has been suggested that an imbalanced microbiome contributes to the development of FC. One potential intervention is post-colonoscopy probiotic supplementation, which could create a favorable environment for FC patients. Objective:: This study aimed to investigate the effect of probiotic supplementation on relieving constipation in FC patients. Methods:: The current study was a double-blinded, randomized, placebo-controlled clinical trial (RCT) involving 78 patients with FC. Participants were randomly assigned to either the probiotic (n=39) or placebo groups (n=39). They received two capsules of either probiotic or placebo for 12 weeks. The assessment of bowel habit was based on ROME-IV criteria, which included anal obstruction feeling, defecation frequency, hard stool, painful defecation, force pushing, manual maneuvers, incomplete emptying, and total score. In addition, primary outcomes also included variables related to the Bristol Stool Form Scale (BSFS). Results:: Probiotic supplementation significantly decreased the ROME-IV total score and its other components, with the exception of defecation frequency, when compared to the placebo group (13.93± 0.57 vs. 17.77± 0.60; P&lt;0.001). Furthermore, the risk of type I stool (RR: 0.036; 95% CI: 0.004-0.331) and II stool (RR: 0.076; 95% CI: 0.019-0.309) was significantly decreased in the probiotic group. Conclusion:: Despite some controversies surrounding the effects of probiotic supplementation on FC treatment, this RCT concluded that probiotic supplementation can improve bowel habits in FC patients. other: Evaluation of the quality of life and fecal count of Lactobacillus and Bifidobacterium can be considered as secondary outcomes for future studies.

Coenzyme Q10 supplementation in burn patients: a double-blind placebo-controlled randomized clinical trial

BackgroundBurn injuries are important medical problems that, aside from skin damage, cause a systemic response including inflammation, oxidative stress, endocrine disorders, immune response, and hypermetabolic and catabolic responses which affect all the organs in the body. The aim of this study was to determine the effect of coenzyme Q10 (CoQ10) supplementation on inflammation, oxidative stress, and clinical outcomes in burn patients.MethodsIn a double-blind placebo-controlled randomized clinical trial, 60 burn patients were randomly assigned to receive 100 mg CoQ10 three times a day (total 300 mg/day) or a placebo for 10 days. Inflammatory markers including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), oxidative stress markers including total antioxidant capacity (TAC), malondialdehyde (MDA) and superoxide dismutase (SOD) activity, fasting blood glucose (FBG), blood urea nitrogen (BUN), creatinine, white blood cells (WBC), and body temperature were assessed as primary outcomes and albumin, prothrombin time (PT), partial thromboplastin time (PTT), international normalized ratio (INR), other hematological parameters, blood pressure, O2 saturation, ICU duration, and 28-mortality rate were assessed as secondary outcomes.ResultsFifty-two participants completed the trial. CRP and ESR levels were not significantly different between CoQ10 and placebo groups at the end of the study (P = 0.550 and P = 0.306, respectively). No significant differences between groups were observed for TAC (P = 0.865), MDA (P = 0.692), and SOD activity (P = 0.633) as well. Administration of CoQ10 resulted in a significant increase in albumin levels compared to placebo (P = 0.031). There was no statistically significant difference between the two groups in other measured outcomes (P > 0.05).ConclusionResults showed that in patients with burn injury, CoQ10 administration had no effect on inflammatory markers and oxidative stress, although serum albumin levels were improved after supplementation. Further studies with albumin as the primary outcome are needed to confirm this finding.

Effects of Pitavastatin on Coronary Artery Disease and Inflammatory Biomarkers in HIV: Mechanistic Substudy of the REPRIEVE Randomized Clinical Trial.

Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. Oral pitavastatin calcium, 4 mg per day. Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. ClinicalTrials.gov Identifier: NCT02344290.

Botulinum toxin-A effects on pain, somatosensory and psychosocial features of patients with refractory masticatory myofascial pain: a randomized double-blind clinical trial

The antinociceptive effect of BoNT-A have been well documented in animal studies; however, results of few but well-designed randomized placebo-controlled clinical trials about BoNT-A efficacy in masticatory myofascial pain (MFP) are inconsistent. Therefore, the present randomized, double-blind, placebo-controlled clinical trial evaluated the efficacy of BoNT-A in patients with refractory MFP. Twenty-eight patients with pain reduction of less than 30% despite conservative treatment and with an average pain intensity of > 50 mm on the visual analogue scale (VAS) participated. Patients were randomly assigned to receive a total of 80 U of BoNT-A or saline solution (SS) injected into the masseter and anterior temporalis muscles. Pain intensity (VAS), quantitative sensory testing (QST), conditioned pain modulation (CPM), and psychosocial status were examined. Follow-up was performed at 1 and 6 months. For repeated-measure comparisons between evaluation times, Friedman test with Bonferroni correction was used for pain and somatosensory variables and the Wilcoxon test for the psychosocial variables. The Mann–Whitney test was used for all comparisons between groups. The BoNT-A group had a significant decrease in pain intensity at follow-ups compared with the SS group (p < 0.001). QST assessment revealed higher pressure pain threshold values in the masseter muscle for BoNT-A group compared to SS (p < 0.03) at all follow-ups. No differences were found for mechanical pain threshold and wind-up ratio values (p > 0.05) in the entire study. The BoNT-A group presented the most efficient CPM effect (p < 0.03) only at the 1 month follow-up in the masseter muscle. There was a significant time effect for BoNT-A in all psychosocial variables (p < 0.05) and a drug effect in the Central Sensitization Inventory (p < 0.01), Pittsburgh Sleep Quality Index (p < 0.004), and Healthy Survey 36 (p < 0.05) at 6 months follow-up. The study demonstrates that a single injection-session of BoNT-A has positive effects on the hall pain spectrum of patients with refractory masticatory myofascial pain.

Is it now appropriate to assert that creatine supplementation holds cognitive benefits for the elderly?

This paper explores the potential cognitive benefits of creatine supplementation for the elderly population. Creatine, known for its role in muscular and neuronal energy metabolism, is primarily obtained through dietary intake, particularly from meat sources. The literature underscores creatine's significance in neural tissue development and cognitive capacity, with deficiencies linked to impaired cognitive function, especially in infants. In the context of the aging global population, cognitive decline is a prevalent concern, and reduced creatine concentration is implicated in this process. While association studies suggest a connection between creatine intake and cognitive performance in the elderly, the absence of robust clinical trials calls for further investigation. Physiological plausibility supports the idea that increased creatine intake, combined with physical activities, could positively impact cognition in the elderly. However, the existing evidence remains inconclusive, and rigorous randomized placebo-controlled clinical trials are essential to establish a cause-and-effect relationship and elucidate underlying mechanisms. Confirmation of cognitive benefits could pave the way for determining optimal dosages to enhance cognitive function in the elderly.

Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19

Treatment options for COVID-19 are warranted irrespective of the presence of risk factors for severe disease. To assess the efficacy and safety of ensitrelvir in patients with mild to moderate COVID-19. This phase 3 part of a phase 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 to July 10, 2022, with a 28-day follow-up period, at 92 institutions in Japan, Vietnam, and South Korea. Patients (aged 12 to <70 years) with mild to moderate COVID-19 within 120 hours of positive viral test results were studied. Patients were randomized (1:1:1) to receive 125 mg of once-daily ensitrelvir (375 mg on day 1), 250 mg of once-daily ensitrelvir (750 mg on day 1), or placebo for 5 days. The primary end point was the time to resolution of the composite of 5 characteristic symptoms of SARS-CoV-2 Omicron infection, assessed using a Peto-Prentice generalized Wilcoxon test stratified by vaccination history. Virologic efficacy and safety were also assessed. A total of 1821 patients were randomized, of whom 1030 (347 in the 125-mg ensitrelvir group, 340 in the 250-mg ensitrelvir group, and 343 in the placebo group) were randomized in less than 72 hours of disease onset (primary analysis population). The mean (SD) age in this population was 35.2 (12.3) years, and 552 (53.6%) were men. A significant difference was observed between the 125-mg ensitrelvir group and the placebo group (P = .04 with a Peto-Prentice generalized Wilcoxon test). The difference in median time was approximately 1 day between the 125-mg ensitrelvir group and the placebo group (167.9 vs 192.2 hours; difference, -24.3 hours; 95% CI, -78.7 to 11.7 hours). Adverse events were observed in 267 of 604 patients (44.2%) in the 125-mg ensitrelvir group, 321 of 599 patients (53.6%) in the 250-mg ensitrelvir group, and 150 of 605 patients (24.8%) in the placebo group, which included a decrease in high-density lipoprotein level (188 [31.1%] in the 125-mg ensitrelvir group, 231 [38.6%] in the 250-mg ensitrelvir group, and 23 [3.8%] in the placebo group). No treatment-related serious adverse events were reported. In this randomized clinical trial, 125-mg ensitrelvir treatment reduced the time to resolution of the 5 typical COVID-19 symptoms compared with placebo in patients treated in less than 72 hours of disease onset; the absolute difference in median time to resolution was approximately 1 day. Ensitrelvir demonstrated clinical and antiviral efficacy without new safety concerns. Generalizability to populations outside Asia should be confirmed. Japan Registry of Clinical Trials Identifier: jRCT2031210350.

Effect of Testosterone on Progression From Prediabetes to Diabetes in Men With Hypogonadism

The effect of testosterone replacement therapy (TRT) in men with hypogonadism on the risk of progression from prediabetes to diabetes or of inducing glycemic remission in those with diabetes is unknown. To evaluate the efficacy of TRT in preventing progression from prediabetes to diabetes in men with hypogonadism who had prediabetes and in inducing glycemic remission in those with diabetes. This nested substudy, an intention-to-treat analysis, within a placebo-controlled randomized clinical trial (Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men [TRAVERSE]) was conducted at 316 trial sites in the US. Participants included men aged 45 to 80 years with hypogonadism and prediabetes or diabetes who were enrolled in TRAVERSE between May 23, 2018, and February 1, 2022. Participants were randomized 1:1 to receive 1.62% testosterone gel or placebo gel until study completion. The primary end point was the risk of progression from prediabetes to diabetes, analyzed using repeated-measures log-binomial regression. The secondary end point was the risk of glycemic remission (hemoglobin A1c level <6.5% [to convert to proportion of total hemoglobin, multiply by 0.01] or 2 fasting glucose measurements <126 mg/dL [to convert to mmol/L, multiply by 0.0555] without diabetes medication) in men who had diabetes. Of 5204 randomized participants, 1175 with prediabetes (mean [SD] age, 63.8 [8.1] years) and 3880 with diabetes (mean [SD] age, 63.2 [7.8] years) were included in this study. Mean (SD) hemoglobin A1c level in men with prediabetes was 5.8% (0.4%). Risk of progression to diabetes did not differ significantly between testosterone and placebo groups: 4 of 598 (0.7%) vs 8 of 562 (1.4%) at 6 months, 45 of 575 (7.8%) vs 57 of 533 (10.7%) at 12 months, 50 of 494 (10.1%) vs 67 of 460 (14.6%) at 24 months, 46 of 359 (12.8%) vs 52 of 330 (15.8%) at 36 months, and 22 of 164 (13.4%) vs 19 of 121 (15.7%) at 48 months (omnibus test P = .49). The proportions of participants with diabetes who experienced glycemic remission and the changes in glucose and hemoglobin A1c levels were similar in testosterone- and placebo-treated men with prediabetes or diabetes. In men with hypogonadism and prediabetes, the incidence of progression from prediabetes to diabetes did not differ significantly between testosterone- and placebo-treated men. Testosterone replacement therapy did not improve glycemic control in men with hypogonadism and prediabetes or diabetes. These findings suggest that TRT alone should not be used as a therapeutic intervention to prevent or treat diabetes in men with hypogonadism. ClinicalTrials.gov Identifier: NCT03518034.

Phytocannabinoids and gingival inflammation: Preclinical findings and a placebo-controlled double-blind randomized clinical trial with cannabidiol.

The aim of this study was to: (1) evaluate the anti-inflammatory effects of cannabidiol (CBD) on primary cultures of human gingival fibroblasts (HGFs) and (2) to clinically monitor the effect of CBD in subjects with periodontitis. The use of phytocannabinoids is a new approach in the treatment of widely prevalent periodontal disease. Cannabinoid receptors were analyzed by western blot and interleukin production detected using enzyme immunoassay. Activation of the Nrf2 pathway was studied via monitoring the mRNA level of heme oxygenase-1. Antimicrobial effects were determined by standard microdilution and 16S rRNA screening. In the clinical part, a placebo-control double-blind randomized study was conducted (56 days) in three groups (n = 90) using dental gel without CBD (group A) and with 1% (w/w) CBD (group B) and corresponding toothpaste (group A - no CBD, group B - with CBD) for home use to maintain oral health. Group C used dental gel containing 1% chlorhexidine digluconate (active comparator) and toothpaste without CBD. Human gingival fibroblasts were confirmed to express the cannabinoid receptor CB2. Lipopolysaccharide-induced cells exhibited increased production of pro-inflammatory IL-6 and IL-8, with deceasing levels upon exposure to CBD. CBD also exhibited antimicrobial activities against Porphyromonas gingivalis, with an MIC of 1.5 μg/mL. Activation of the Nrf2 pathway was also demonstrated. In the clinical part, statistically significant improvement was found for the gingival, gingival bleeding, and modified gingival indices between placebo group A and CBD group B after 56 days. Cannabidiol reduced inflammation and the growth of selected periodontal pathogenic bacteria. The clinical trial demonstrated a statistically significant improvement after CBD application. No adverse effects of CBD were reported by patients or observed upon clinical examination during the study. The results are a promising basis for a more comprehensive investigation of the application of non-psychotropic cannabinoids in dentistry.

P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials

Abstract Background Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD). Methods MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P&amp;lt;0.05) associated with placebo rates were identified using regression analyses. Results Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission. Conclusion Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.

Placebo-controlled randomized clinical trials of antidepressants for major depressive disorder: Analysis of ClinicalTrials.gov, 2008–2022

The purpose of this study was to analyze the key aspects of the design of contemporary placebo-controlled randomized clinical trials (RCTs) of antidepressants enrolling patients with major depressive disorder (MDD) aged 18 years or older, especially the outcome measures and the eligibility criteria. The study included 122 RCTs registered with ClinicalTrials.gov and started from 2008 through 2022. Most RCTs assessed only clinical remission, with proportion of trials with outcome measures related to functional remission being rather low (n = 34; 28 %). Clinical remission was mostly evaluated in acute phase of depression, and only 7 (6 %) trials assessed the prevention of relapse. Proportion of trials utilizing self-report questionnaires that provide important information complementary to clinician-rated scales was moderate (n = 66; 54 %). Another problem in included RCTs was common use of stringent eligibility criteria. For instance, minimal symtpom severity required for the patient's inclusion was listed in 104 RCTs (85 %), and 41 RCTs (34 %) excluded patients based on comorbid anxiety disorders. Most RCTs (n = 103; 84 %) excluded older patients, and only 6 (5 %) trials were dedicated exclusively to them. To ensure optimal development of clinical pharmacotherapy of MDD, the investigators should consider modification of some of the key aspects of the design of RCTs of antidepressants.

Immunogenicity and reactogenicity following MMR vaccination in 5–7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants

Measles is a highly contagious viral disease. Vaccinated mothers transfer fewer antibodies during pregnancy, resulting in shortened infant immunity. Earlier primary vaccination might avert the gap in protection. Healthy 5-7-month-old Danish infants were assigned in a 1:1 ratio to M-M-RVaxPro or placebo (solvent) in a double-blind, randomized trial between April 15, 2019 and November 1, 2021 (ClinicalTrials.govNCT03780179, EudraCT 2016-001901-18). Eligibility criteria were birth weight >1000g and gestational age ≥32 weeks.Immunogenicity was measured by plaque reduction neutralization test (PRNT) and IgG ELISA before intervention, four weeks after intervention and routine MMR. Reactogenicity data were collected for six weeks and measured by hazard ratios (HR). 647 and 6540 infants participated in the immunogenicity and reactogenicity study, respectively; 87% and 99% completed follow-up. After early MMR, seroprotection rates (SPRs) were 47% (13%) in measles PRNT; 28% (2%), 57% (8%) in mumps and rubella IgG (placebo). For measles PRNT, geometric mean ratio was 4.3 (95% CI: 3.4-5.3) between randomization groups after intervention and 1.5 (95% CI: 1.3-1.9) after routine MMR.Reactogenicity was independent of randomization (HR, 1.0; 95% CI: 0.9-1.1). Severe adverse events occurred in 25 infants (HR, 1.8; 95% CI: 0.8-4.0); none deemed vaccine related. Early MMR elicited low SPRs but did not negatively impact short-term responses to a subsequent MMR. MMR at 5-7 months was safe and not associated with higher rates of reactogenicity than placebo. Innovation Fund Denmark.

Preoperative Midazolam and Patient-Centered Outcomes of Older Patients

The effect of oral midazolam premedication on patient satisfaction in older patients undergoing surgery is unclear, despite its widespread use. To determine the differences in global perioperative satisfaction in patients with preoperative administration of oral midazolam compared with placebo. This double-blind, parallel-group, placebo-controlled randomized clinical trial was conducted in 9 German hospitals between October 2017 and May 2019 (last follow-up, June 24, 2019). Eligible patients aged 65 to 80 years who were scheduled for elective inpatient surgery for at least 30 minutes under general anesthesia and with planned extubation were enrolled. Data were analyzed from November 2019 to December 2020. Patients were randomized to receive oral midazolam, 3.75 mg (n = 309), or placebo (n = 307) 30 to 45 minutes prior to anesthesia induction. The primary outcome was global patient satisfaction evaluated using the self-reported Evaluation du Vécu de l'Anesthésie Generale (EVAN-G) questionnaire on the first postoperative day. Key secondary outcomes included sensitivity and subgroup analyses of the primary outcome, perioperative patient vital data, adverse events, serious complications, and cognitive and functional recovery up to 30 days postoperatively. Among 616 randomized patients, 607 were included in the primary analysis. Of these, 377 (62.1%) were male, and the mean (SD) age was 71.9 (4.4) years. The mean (SD) global index of patient satisfaction did not differ between the midazolam and placebo groups (69.5 [10.7] vs 69.6 [10.8], respectively; mean difference, -0.2; 95% CI, -1.9 to 1.6; P = .85). Sensitivity (per-protocol population, multiple imputation) and subgroup analyses (anxiety, frailty, sex, and previous surgical experience) did not alter the primary results. Secondary outcomes did not differ, except for a higher proportion of patients with hypertension (systolic blood pressure ≥160 mm Hg) at anesthesia induction in the placebo group. A single low dose of oral midazolam premedication did not alter the global perioperative patient satisfaction of older patients undergoing surgery or that of patients with anxiety. These results may be affected by the low dose of oral midazolam. Further trials-including a wider population with commonplace low-dose intravenous midazolam and plasma level measurements-are needed. ClinicalTrials.gov Identifier: NCT03052660.

Effect of Esketamine Added to Propofol Sedation on Desaturation and Hypotension in Bidirectional Endoscopy

Propofol sedation is widely used for endoscopic procedures, but it poses risks of hemodynamic and respiratory depression. The addition of esketamine as an adjuvant may reduce propofol requirements and associated adverse events. To evaluate the effects of low-dose esketamine added to propofol-based sedation on desaturation and hypotension during same-visit bidirectional endoscopy. This multicenter, double-blind, placebo-controlled randomized clinical trial assessed patients from 3 teaching hospitals in China who were scheduled for same-visit bidirectional endoscopy between February 8 and November 30, 2022, and randomly assigned to receive esketamine or normal saline (placebo). After induction of sedation with 0.1 μg/kg of sufentanil and 0.5 mg/kg of propofol, patients in the esketamine group received 0.15 mg/kg of intravenous esketamine, whereas patients in the placebo group received an equivalent volume of saline. Sedation was achieved through propofol titration. The primary outcome was the composite of desaturation and hypotension during the procedures. Secondary outcomes included desaturation, hypotension, propofol requirements, postprocedure pain and fatigue, nausea or vomiting, dizziness or headache, hallucination or nightmare, endoscopist satisfaction, and patient satisfaction. Among the 663 initially enrolled patients, 660 completed the study (median [IQR] age, 48 [36-57] years; 355 [53.8%] female), with 331 randomized to the esketamine group and 329 to the placebo group. The administration of esketamine compared with placebo significantly reduced the incidence of the composite outcome of desaturation and hypotension (8.2% vs 21.0%; difference, -12.8 percentage points; odds ratio [OR], 0.34; 95% CI, 0.21-0.54; P < .001). Additionally, esketamine led to significantly lower incidences of desaturation (OR, 0.36; 95% CI, 0.18-0.72; false discovery rate q = .01) and hypotension (OR, 0.33; 95% CI, 0.18-0.60; q < .001) and reduced propofol requirements (difference, -58.9 mg; 95% CI, -65.7 to -52.2 mg; q < .001), without significant effects on other secondary outcomes. In this randomized clinical trial of patients undergoing same-visit bidirectional endoscopy, the administration of low-dose esketamine resulted in an approximately 61% reduction in the incidence of desaturation and hypotension, accompanied by decreased propofol requirements. These findings support the use of esketamine as an adjuvant to propofol-based sedation in endoscopic procedures. Chinese Clinical Trial Registry Identifier: ChiCTR2200055938.

Ketamine for postoperative avoidance of depressive symptoms: the K-PASS feasibility randomised trial

BackgroundSurgical patients with previous depression frequently experience postoperative depressive symptoms. This study's objective was to determine the feasibility of a placebo-controlled trial testing the impact of a sustained ketamine infusion on postoperative depressive symptoms. MethodsThis single-centre, triple-blind, placebo-controlled randomised clinical trial included adult patients with depression scheduled for inpatient surgery. After surgery, patients were randomly allocated to receive ketamine (0.5 mg kg−1 over 10 min followed by 0.3 mg kg−1 h−1 for 3 h) or an equal volume of normal saline. Depressive symptoms were measured using the Montgomery–Asberg Depression Rating Scale. On post-infusion day 1, participants guessed which intervention they received. Feasibility endpoints included the fraction of patients approached who were randomised, the fraction of randomised patients who completed the study infusion, and the fraction of scheduled depression assessments that were completed. ResultsIn total, 32 patients were allocated a treatment, including 31/101 patients approached after a protocol change (31%, 1.5 patients per week). The study infusion was completed without interruption in 30/32 patients (94%). In each group, 7/16 participants correctly guessed which intervention they received. Depression assessments were completed at 170/192 scheduled time points (89%). Between baseline and post-infusion day 4 (pre-specified time point of interest), median depressive symptoms decreased in both groups, with difference-in-differences of −1.00 point (95% confidence interval −3.23 to 1.73) with ketamine compared with placebo. However, the between-group difference did not persist at other time points. ConclusionsPatient recruitment, medication administration, and clinical outcome measurement appear to be highly feasible, with blinding maintained. A fully powered trial may be warranted. Clinical trial registrationNCT05233566.

Oral Acitretin Plus Topical Triamcinolone vs Topical Triamcinolone Monotherapy in Patients With Symptomatic Oral Lichen Planus

Symptomatic oral lichen planus (OLP) can be challenging to treat. To compare the efficacy of oral acitretin plus topical triamcinolone acetonide (TAC), 0.1%, with TAC monotherapy in patients with symptomatic OLP. This monocentric, investigator-initiated, placebo-controlled, investigator- and patient-blinded randomized clinical trial was conducted from December 2018 to June 2020 at the Postgraduate Institute of Medical Education and Research, a tertiary referral center in Chandigarh, India. Sixty-four patients 18 years or older with symptomatic OLP were recruited by consecutive sampling. Data were analyzed from July to December 2020. The patients were randomized to receive either a combination of oral acitretin (25-35 mg/d) and TAC (treatment group) or TAC in combination with placebo (placebo group) for 28 weeks, with an additional 8 weeks of treatment-free follow-up after the end of treatment (36 weeks of total study duration). The disease severity and treatment response were assessed using Oral Disease Severity Score (ODSS), Oral Health Impact Profile 14 (OHIP-14), and visual analog scale (VAS). The primary aim was to assess the number of patients achieving ODSS-75 (75% reduction in ODSS compared with baseline) in both groups at 28 weeks and at the end of 36 weeks. Among 64 patients, 31 in the treatment group and 30 in the placebo group completed the study (mean [SD] age, 50.6 [15.2] years vs 49.2 [14.4] years; male-female ratio, 13:19 vs 16:16). Baseline ODSS, visual analog scale, and Oral Health Impact Profile 14 scores were comparable in both groups. In the intention-to-treat analysis, there was a statistically significant higher number of patients achieving 75% or higher reduction in ODSS in the treatment group compared with the placebo group at the end of 28 weeks (28 [88%] vs 15 [47%], a 41 [95% CI, 20-61] percentage point difference between groups; P < .001; Cramér V = 0.47) and 36 weeks (27 [84%] vs 13 [41%], a 43 [95% CI, 23-67] percentage point difference between groups; P < .001; Cramér V = 0.47). Relapses during the posttreatment follow-up of 8 weeks were low among patients in both treatment and placebo groups (1 [3%] vs 2 [6%], a 3 [95% CI, -13 to 7] percentage point difference between groups; P > .99; Cramér V = 0.07). In this randomized clinical trial, the combination of oral acitretin and TAC was more effective than TAC monotherapy in patients with symptomatic OLP. Clinical Trial Registry of India Identifier: CTRI/2018/11/016448.